Project Two: Identification of modifiers of fibrosis based on differential genetic backgrounds in mice

PIs:

Elizabeth McNally
Stanley Nelson

Muscular dystrophy arises from defects in many different single genes. Mutations in the genes
encoding dystrophin or the sarcoglycans elicit a phenotype of progressive muscle weakness accompanied by dilated cardiomyopathy. The relationship between dystrophin and sarcoglycan gene mutations is further reinforced by the assembly of these proteins into the dystrophin glycoprotein complex (DGC). The DGC plays a key role in stabilizes the plasma membrane against the forces associated with repetitive contraction. As both cardiac and skeletal muscle face repeated contraction, both heart and muscle are damaged by loss of dystrophin and sarcoglycan. Mutations in γ-sarcoglycan lead to a recessive form of muscular dystrophy, similar to what occurs in Duchenne Muscular Dystrophy (DMD). There is a single mutation in the gene encoding γ-sarcoglycan, Sgcg 521ΔT, that has been described in LGMD patients from around the world. Despite the presence of the identical gene mutation, there is considerable phenotypic variability with this mutation. Similarly, with identical DMD mutations, brothers sharing the same mutation may have a discrepant disease process. We sought to identify genes that modify the outcome of limb-based disease in muscular dystrophy using a mouse model of γ-sarcoglycan mutations, Sgcg null. We selected this model because of the strong evidence for genetic modifiers in the corresponding human disease and because we reasoned that such modifiers could point to pathways that may be useful for therapeutic intervention. Using the Sgcg null model, we identified Ltpb4, a TGFβ binding protein, as a modifier of muscle disease. We mapped modifiers of muscular dystrophy by using two distinct background strains, D2 and 129, that lead to severe and mild forms of muscle disease, respectively. We now are using a similar strategy to understand modifiers of cardiac function in muscular dystrophy.